The immune mechanisms that underlie the pathogenesis and/or regulation of human autoimmune diseases represent a very important but significantly understudied aspect of human disease. Our understanding of autoimmunity and its intrinsic regulation derives from extensive work in animal models that may or may not reflect essential aspects of the human disease. As a result, most of the upcoming therapeutic strategies are also based on this body of knowledge. Moreover, we have very limited mechanistic insights into how currently used immune therapeutic approaches mediate their myriad immune effects in the human disease setting. To develop better diagnostic and treatment strategies, it is critical to study human immune disease directly and to dissect the mechanisms of immune therapies as best as can be done, given the constraints of the clinical situation. This would not only provide invaluable insights, but would allow us to develop better models of these diseases incorporating under-represented aspects of the disease. With that in the mind, the principal investigator (PI) has built a career in patient-oriented research, specifically focusing on the processes that underlie immune-mediated diseases and their therapies. This K24 mid-career investigator award will provide the PI with the resources and the protected time to mentor physician-scientists at various stages of their careers in this area of research. The major focus of the PI's laboratory is the immunology of multiple sclerosis, an immune-mediated demyelinating disease of the central nervous system. The studies proposed here will apply current knowledge about the MS immune system to develop a diagnostic laboratory test for the immunologic monitoring of this disease. Other collaborative projects available for appropriate trainees include the dissection of immune dysregulation underlying hepatitis C virus infection, the pre-clinical validation of therapeutic allodepletion for minimizing graft-versus-host disease and diagnostic issues in hematologic and immunologic diseases. The PI's own division and department have large residency and fellowship programs (including both MD/PhD and MD candidates) as well as junior faculty with a particular interest in research. He is an active participant in several collaborative teams spanning multiple departments and has a track record of mentoring MSTP students, residents, fellows and junior faculty in the departments of pathology, neurology and internal medicine. The environment at UT Southwestern provides outstanding support for the development of this program, with multiple internal mechanisms of support and infrastructure already in place. This award will greatly facilitate the ability to train the next generation of scientists in this important NIAID endeavor.